The Search for Schizophrenia Genes Takes an
Unplanned Turn

By Trent StocktonJohns Hopkins Medicine

Despite promising evidence that a gene closely linked
to schizophrenia would be found on human chromosome No. 1,
an international team of scientists who scoured the
chromosome in more than 1,900 patients concludes it isn't
there. "The bad news is we couldn't find it, but the good
news is we can now concentrate on other regions of the
genome, such as chromosomes 6, 8 and 13," says Ann Pulver,
associate professor of
psychiatry at Johns Hopkins and co-author of the
study.

The gene hunters' findings, published in the April 26
issue of Science, highlight the challenge of identifying the
genetic roots of complex diseases.

"Schizophrenia is a complex psychiatric disorder,"
Pulver says. "It can't be explained by either a single
altered gene or a single environmental cause. There are
clearly genetic components, but they are likely to be varied
and to interact in many ways with nongenetic factors."

Recent studies had suggested that genes associated with
susceptibility to schizophrenia would be found on the "q" or
long arm of chromosome 1, a region separated from the short
arm, known as "p."

In their study, Pulver and colleagues searched for
associations between genetic markers on chromosome 1 and
schizophrenia in families that have more than one member
with the disease. This approach, called genetic linkage
analysis, is used to detect the location on the chromosome
where disease genes reside.

"By pooling our resources and data, and agreeing on how
to attack the problem in a large sample of affected
families, we were able to quickly use this type of genetic
linkage analysis to tell if we were on the right track,"
Pulver says.

It's still possible that genes on chromosome 1q
contribute to the disease, she says, but these would
influence only a small proportion of patients. "Biology is
complicated, and the search for genes that contribute to
large numbers of cases continues," she says.

Solomon Snyder, University Distinguished Professor of
Neuroscience,
Pharmacology and
Psychiatry, says, "This paper highlights the difficulty
of unraveling complex diseases." Snyder is an author, with
Akira Sawa, of a review article on schizophrenia research in
the same issue of Science.

Snyder points out that a variety of genetic and
environmental factors are at play in cancer, cardiovascular
disorders and diabetes. "Despite the difficulties," Snyder
says, "we are getting closer to understanding the molecular
causes of schizophrenia. Advances in imaging, neuroanatomy,
genetic analysis and psychopharmacology are being applied in
earnest to this debilitating disease."

The study was funded by the National Institute of
Mental Health, Medical Research Council (UK), Deutsche
Forschungsfemeinschaft, the German-Israeli Foundation for
Scientific Research, the National Health and Medical
Research Council of Australia and the Centre National de la
Recherche Scientifique. The lead author of the study is
Douglas Levinson, Department of Psychiatry, University of
Pennsylvania. Other Hopkins scientists involved in the study
are Gerald Nestadt and Kung Yee Liang.